Cancer development is a multistage process that results from the step-wise acquisition of genetic alterations. These alterations may involve the dysregulation of a variety of normal cellular functions, leading to the initiation and progression of cancer cells. Cancer cells bear an indefinite proliferative capacity and are able to elude the commitment to terminal differentiation and quiescence that regulates normal tissue homeostasis.
The human epidermal growth factor receptor (HER/ErbB) family consists of the receptors EGFR (ErbB1), HER2 (ErbB2), HER3(ErbB3) and HER4 (ErbB4). The receptors can activate numerous downstream signaling pathways in response to extracellular ligands and regulate diverse cellular processes including differentiation, migration, proliferation, and survival. Members of the epidermal growth factor receptor family are over-expressed in many types of human cancers (e.g., Normanno et al., 2006, Gene 366, 2-16). In addition, mutational activation of members of the EGFR family has been observed in a variety of human malignancies (e.g., Charpidou et al., 2008, In vivo 22: 529-536). Suppressing the activity of EGFR receptors, for instance through the administration of receptor tyrosine kinase inhibitors, has provided new methods of anti-cancer therapy.
Heparin-Binding Epidermal Growth Factor-like growth factor (HB-EGF) is a ligand for the EGFR family of receptors that can bind and activate all members of the EGFR family of receptors (See e.g., Elenius et al., 1997, EMBO J 16:1268-1278; Johnson et al., 2005, J Cell Physiol 205:218-227). While there are a variety of ligands that can activate members of the EGFR family of receptors, only HB-EGF is abundantly expressed in many types of cancers including ovarian, gastric, pancreatic, renal, lung, prostate, and breast cancer, melanoma and glioblastoma. HB-EGF has also been shown to play a key role in the acquisition of malignant phenotypes, such as cell survival, peritoneal fluid, cell adhesion on extracellular matrices, invasion, angiogenesis, tumorigenicity and chemoresistance in cancer (Ongusaha et al., 2004, Cancer Res 64: 5283).